Peripheral regulatory T cells and anti-inflammatory cytokines in children with juvenile idiopathic arthritis

  • Katarzyna Sznurkowska Department of Pediatrics, Pediatric Gastroenterology Hepatology and Nutrition, Medical University of Gdańsk http://orcid.org/0000-0003-2502-0027
  • Małgorzata Boćkowska Department of Pediatric Rheumatology, Provincial Center of Rheumatology in Sopot
  • Maciej Zieliński Department of Clinical Immunology and Transplantology, Medical University of Gdansk
  • Katarzyna Plata-Nazar Department of Pediatrics, Pediatric Gastroenterology Hepatology and Nutrition, Medical University of Gdańsk
  • Piotr Trzonkowski Department of Clinical Immunology and Transplantology, Medical University of Gdansk
  • Anna Liberek Faculty of Health Sciences with Subfaculty of Nursing, Medical University of Gdansk
  • Barbara Kamińska Department of Pediatrics, Pediatric Gastroenterology, Hepatology and Nutrition, Medical University of Gdańsk
  • Agnieszka Szlagatys-Sidorkiewicz Department of Pediatrics, Pediatric Gastroenterology, Hepatology and Nutrition, Medical University of Gdańsk
Keywords: T-regulatory cells, Interleukin 10, Transforming Growth Factor β1, juvenile idiopathic arthritis

Abstract

Background Juvenile idiopathic arthritis (JIA) is a chronic, heterogenous inflammatory disease of unclear pathogenesis. JIA is hypothesized to be linked to a defective immune regulation. Anti-inflammatory cytokines belong to the best known regulatory factors. T-regulatory cells are a crucial cellular component of immune tolerance. One of their functions is synthesis of interleukin 10 (IL-10) and transforming growth factor beta1 (TGF-ß1).The aim of this study was to determine the proportion of T-regulatory cells (CD4+CD25highFOXP3+) in peripheral blood, and serum levels of TGF-ß1 and IL-10 in patients with JIA.Methods: The study included 25 patients with newly diagnosed JIA: oligoarthritis (n=17) and polyarthritis (n=8). Control group was comprised of 17 healthy children. CD4+CD25highFOXP3+ T cells in peripheral blood were quantified by means of three-color flow cytometry. Serum concentrations of TGF-ß1 and IL-10 were estimated with ELISA.Results: The proportion of peripheral CD4+CD25highFOXP3+cells in patients with JIA was significantly higher than in the controls (p=0.04). The two groups did not differ significantly in terms of their TGF-ß1 and IL-10 concentrations.Conclusions: At the time of the diagnosis, children with JIA present with elevated proportion of T-regulatory cells (CD4+CD25highFOXP3+) in peripheral blood. Anti-inflammatory cytokines, IL-10 and TGF-ß1, are not upregulated in the serum of patients with JIA, and therefore should not be considered as biomarkers of this condition.

Author Biographies

Małgorzata Boćkowska, Department of Pediatric Rheumatology, Provincial Center of Rheumatology in Sopot
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Maciej Zieliński, Department of Clinical Immunology and Transplantology, Medical University of Gdansk
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Katarzyna Plata-Nazar, Department of Pediatrics, Pediatric Gastroenterology Hepatology and Nutrition, Medical University of Gdańsk
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Piotr Trzonkowski, Department of Clinical Immunology and Transplantology, Medical University of Gdansk
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Anna Liberek, Faculty of Health Sciences with Subfaculty of Nursing, Medical University of Gdansk
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Barbara Kamińska, Department of Pediatrics, Pediatric Gastroenterology, Hepatology and Nutrition, Medical University of Gdańsk
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Agnieszka Szlagatys-Sidorkiewicz, Department of Pediatrics, Pediatric Gastroenterology, Hepatology and Nutrition, Medical University of Gdańsk
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References

References

Consolaro A, Ruperto N, Bazso A, Pistorio A, Magni-Manzoni S, Filocamo G, Malattia C, Viola S, Martini A, Ravelli A (2009) Development and validation of a composite disease activity score for juvenile idiopathic arthritis. Arthritis Rheum 61:658-66. http//doi.org/ 10.1002/art.24516

Cush JJ, Splawski JB, Thomas R, McFarlin JE, Schulze-Koops H, Davis LS, Fujita K, Lipsky PE (1995) Elevated interleukin-10 levels in patients with rheumatoid arthritis. Arthritis Rheum 38: 96-104

de Kleer IM, Wedderburn LR, Taams LS, Patel A, Varsani H, Klein M, de Jager W, Pugayung G, Giannoni F, Rijkers G, Albani S, Kuis W, Prakken B ( 2004) +CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J Immunol 172:6435-43

Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G (2001) Ex Vivo Isolation and Characterization of CD4+ CD25+ T Cells with Regulatory Properties from Human Blood. J Exp Med 193:1303–1310. http//doi.org/ 10.1084/jem.193.11.1303

Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, Mauri C (2004) Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF alpha therapy. Journal of Experimental Medicine 200:277-85

Gonzalo-Gil E, Galindo-Izquierdo M (2014) Role of transforming growth factor-beta (TGF) beta in the physiopathology of rheumatoid arthritis. Reumatol Clin 10:174-9. http//doi.org/ 10.1016/j.reuma.2014.01.009

Guidi L, Felice C, Procoli A, Bonanno G, Martinelli E, Marzo M, Mocci G, Pugliese D, Andrisani G, Danese S, de Vitis I, Papa A, Armuzzi A, Rutella S (2013) FOXP3(+) T regulatory cell modifications in inflammatory bowel disease patients treated with anti-TNFalpha agents. Biomed Res Int 286368. http//doi.org/ 10.1155/2013/286368

Han GM, O'Neil-Andersen NJ, Zurier RB, Lawrence DA (2008) CD4+CD25high T cell numbers are enriched in the peripheral blood of patients with rheumatoid arthritis. Cell Immunol 253:92–101. http//doi.org/ 10.1016/j.cellimm.2008.05.007

Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057-1061. http//doi.org/ 10.1126/science.1079490

Huang X, Zhu J, Yang Y (2005). Protection against autoimmunity in nonlymphopenic hosts by CD4+ CD25+ regulatory T cells is antigen-specific and requires IL-10 and TGF-beta. J Immunol 175 : 4283-91

Ji L, Geng Y, Zhou W, Zhang Z (2013) A study on relationship among apoptosis rates, number of peripheral T cell subtypes and disease activity in rheumatoid arthritis. Int J Rheum Dis 19:167-71. http//doi.org/ 10.1111/1756-185X.12211

Jiao Z, Wang W, Jia R, Li J, You H, Chen L, Wang Y (2007) Accumulation of FoxP3-expressing CD4+CD25+ T cells with distinct chemokine receptors in synovial fluid of patients with active rheumatoid arthritis. Scand J Rheum 36:428–433. http//doi.org/ 10.1080/03009740701482800

Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH ( 2001) Identification and Functional Characterization of Human CD4+ CD25+ T Cells with Regulatory Properties Isolated from Peripheral Blood. J Exp Med 193:1285–1294. http//doi.org/ 10.1084/jem.193.11.1285.

Katsikis PD, Chu CQ, Brennan FM, Maini RN, Feldmann M.(1994) Immunoregulatory role of interleukin 10 in rheumatoid arthritis. J Exp Med 179:1517–27

Kawakami A, Eguchi K, Matsuoka N, Tsuboi M, Urayama S, Kawabe Y, Aoyagi T, Maeda K, Nagataki S (1997) Inhibitory effects of interleukin-10 on synovial cells of rheumatoid arthritis. Immunology: 91:252–259

Kugathasan S, Saubermann LJ, Smith L, Kou D, Itoh J, Binion DG, Levine AD, Blumberg RS, Fiocchi C (2007) Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease. Gut 56:1696-1705

Lawson CA , Brown AK, Bejarano V, Douglas SH, Burgoyne CH, Greenstein AS, Boylston AW, Emery P, Ponchel F, Isaacs JD (2006) Early rheumatoid arthritis is associated with a deficit in the CD4+CD25high regulatory T cell population in peripheral blood reactive. Rheumatology (Oxford) 45:1210-7

Li MO, Flavell RA (2008) Contextual Regulation of Inflammation: A Duet by Transforming Growth Factor-b and Interleukin-10. Immunity 28(4):468-76. http//doi.org/ 10.1016/j.immuni.2008.03.003

Lin SC, Chen KH, Lin CH, Kuo CC, Ling QD, Chan CH (2007) The quantitative analysis of peripheral blood FOXP3-expressing T cells in systemic lupus erythematosus and rheumatoid arthritis patients Eur J Clin Invest 37: 987–996, http//doi.org/ 10.1111/j.1365-2362.2007.01882.x

Liu MF, Wang CR, Fung LL, Lin LH, Tsai CN (2005) The presence of cytokine-suppressive CD4+CD25+ T cells in the peripheral blood and synovial fluid of patients with rheumatoid arthritis. Scand J Immunol 62: 312–317

Muñoz-Valle JF, Torres-Carrillo NM, Guzmán-Guzmán IP, Torres-Carrillo N, Ruiz-Quezada SL, Palafox-Sánchez CA, Rangel-Villalobos H, Ramírez-Dueñas MG, Parra-Rojas I, Fafutis-

Morris M, Bastidas-Ramírez BE, Pereira-Suárez AL (2012) The functional class evaluated in rheumatoid arthritis is associated with soluble TGF-β1 serum levels but not with G915C (Arg25Pro) TGF-β1 polymorphism Rheumatol Int 32: 367–372. http//doi.org/ 10.1007/s00296-010-1624-x

Nordal EB, Zak M, Berntson L, Aalto K, Lahdenne P, Peltoniemi S, Nielsen S, Herlin T, Straume B, Fasth A, Rygg M (2011) Juvenile Arthritis Disease Activity Score (JADAS) based on CRP; validity and predictive ability in a Nordic population-based setting. Pediatr Rheumatol Online J 9: P155. http//doi.org/ 10.1186/1546-0096-9-S1-P155

Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, He X, Maldonado-Cocco J, Orozco-Alcala J, Prieur AM, Suarez-Almazor M, Woo P (2004). International League of Associations for Rheumatology classification of idiopathic juvenile arthritis, second revision, Edmonton, 2001. J Rheumatol 31: 390-2

Prahalad S, Martins TB, Tebo AE, Whiting A, Clifford B, Zeft AS, McNally B, Bohnsack JF, Hill HR (2008) Elevated serum levels of soluble CD154 in children with juvenile idiopathic arthritis. Pediatr Rheumatol Online 28:6:8 http//doi.org/ 10.1186/1546-0096-6-8

Ravelli A, Martini A (2007) Juvenile idiopathic arthritis. Lancet 369:767–778.http//doi.org/ 10.1016/S0140-6736(07)60363-8

Sempere-Ortells JM, Pérez-García V, Marín-Alberca G, Peris-Pertusa A, Benito JM, Marco FM, Zubcoff JJ, Navarro- Blasco FJ (2009) Quantification and phenotype of regulatory T cells in rheumatoid arthritis according to disease activity Score-28. Autoimmunity 42:636–645. http//doi.org/ 10.3109/08916930903061491

Stelmaszczyk-Emmel A, Jackowska T, Rutkowska-Sak L, Marusak-Banacka M, Wąsik M (2012) Identification, frequency, activation and function of CD4+ CD25highFoxP3+ regulatory T cells in children with juvenile idiopathic arthritis. Rheumatol Int 32: 1147–1154. http//doi.org/ 10.1007/s00296-010-1728-3

Strauss L, Bergmann C, Szczepanski M, Gooding W, Johnson JT, Whiteside TL ( 2007) A Unique Subset of CD4+CD25highFoxp3+ T Cells Secreting Interleukin-10 and Transforming Growth Factor-β1 Mediates Suppression in the Tumor Microenvironment. Clin Cancer Res 13 :4345-54. http//doi.org/ 10.1158/1078-0432.CCR-07-0472

Szymańska-Kałuża J, Cebula-Obrzut B, Smolewski P, Stanczyk J, Smolewska E (2014) Imbalance of Th17 and T-regulatory cells in peripheral blood and synovial fluid in treatment naïve children with juvenile idiopathic arthritis. Centr Eur J Immunol 39: 71-76. http//doi.org/ 10.5114/ceji.2014.42128

van Amelsfort JMR, Jacobs KMG, Bijlsma JWJ, Lafeber FPJG, Taams LS (2004) CD4+CD25+ regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum 50: 2775–85. http//doi.org/ 10.1002/art.20499

Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA (2001) A role for TGF-beta generation

and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J Immunol 166:7282-9

Published
2018-05-27
Section
Articles